MM has a dismal prognosis, with a median survival of about 1 year. The current mainstays of MM therapy are represented by surgery—mostly palliative, and platinum-based chemotherapy combined with pemetrexed [
54]. Recently, the addition of the angiogenesis inhibitor bevacizumab resulted in a marginal increase in overall survival [
55]. Novel therapeutic agents are therefore needed to tackle this deadly disease.
The development of new therapeutic agents for rare cancers, such as MM, is hampered by the increasing costs of research and drug development from the laboratory to the patient’s bed [
56]. Drug repurposing, which involves finding new uses for existing drugs that are outside the scope of their original indication, is a strategy that drastically reduces time and costs to bring a new drug to the market.
The anti-neoplastic properties of FTY720 are well established and evidences for repurposing this agent have been recently proposed [
22]. Effects of FTY720 as a single agent or in combination with chemotherapy have been shown in a wide variety of cancer models, such as leukemia, colorectal, lung, brain and breast cancers [
22]. So far, the efficacy and mode of action of FTY720 in MM, has not been thoroughly investigated. In this study we show that FTY720 effectively reduced MM growth both in vitro and in vivo as a single agent. Our data indicate that, in MM, FTY720 significantly inhibited the enzymatic activity of the oncogene SphK1 and reactivated the tumor suppressor activity of PP2A, suggesting that FTY720 anti-tumor activity may be exerted via modulation of these effectors. SphK1 has been previously reported to be upregulated in MM [
35]. Here we show that MM cells exhibit PP2A inactivation, associated with overexpression of PP2A inhibitory proteins SET and CIP2A, indicating that PP2A may be involved in MM malignancy. Indeed, animal studies have shown that inactivation of PP2A by the SV40 small-t tumor antigen is required for SV40-mediated transformation of primary human mesothelial cells in tissue culture and for SV40-induced MMs in hamsters [
57‐
59]. A number of studies indicate that alterations of PP2A and SphK1 (namely, inhibition of the former and overexpression of the latter) cooperate in the activation of pro-survival pathways in cancer [
60‐
62]. Here we show that FTY720 caused inhibition of AKT phosphorylation and reduced the levels of anti-apoptotic Bcl-2 protein, leading to programmed cell death. Overall our mechanistic data provide a solid rationale for the therapeutic efficacy of FTY720 observed in MM.
Since the discovery of its potent anticancer activity, repurposing of FTY720 is being considered for cancer patient treatment [
22,
56]. Efficacy and bio-safety profiles of FTY720 are well described in multiple sclerosis (MS) patients [
63]. In cancer therapy applications, its possible undesired effects and the interference of its immunosuppressive activities are recognized [
22,
56]. Toxicity and efficacy trade-offs are not straightforward in cancer treatment: the actual toxicity associated with the use of a drug depends on many factors including the duration and treatment regimen, as well as patient characteristics, such as tumor staging, age and other co-morbidity factors. However, in highly aggressive and resistant cancers, such as MM, the survival benefits obtained administering an effective anticancer drug, may outweigh the risks of toxicity. A recent meta-analysis study of safety and toxicity of FTY720, designed to investigate its potential use in the treatment of chronic myeloid leukemia, suggested that this drug has an acceptable risk to benefit ratio, given its lack of bone marrow toxicity and relatively low rate of serious side effects [
64]. In future, biomarker studies aimed to identify those patients that may be more likely to benefit from FTY720 therapy, would help target this drug to a selected patient subpopulation, where benefits outweigh risks [
65‐
67]. To note, the side effects of FTY720 are reversible upon treatment withdrawal, at least at the doses used in MS patients [
68], therefore, a design of a specific on/off schedule may mitigate the adverse effects. Moreover, a number of different strategies are being developed to minimize FTY720 side effects, such as nanoparticle delivery, combination therapies and design of new derivatives of FTY720. Most importantly, the adverse effects of FTY720 are attributed to its phosphorylated isoform, FTY720-P, while the anti-cancer effects, exerted via interaction with targets, such as SET-PP2A and SphK1, have been specifically associated with the unphosphorylated form of FTY720 [
32,
46]. Accordingly, unphosphorylatable second-generation derivatives of FTY720 have been developed and are being extensively studied in preclinical cancer models (e.g. OSU-2S0 [
69]). As compared to FTY720, these appear to possess a stronger anti-cancer effect, while lacking systemic immunosuppressive properties [
69]. Such derivatives should eliminate concerns related to immune suppression and represent a novel promising therapeutic strategy for MM.